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Background <p>T-cell immunoglobulin and mucin domain 3 (Tim-3) is a critical immune checkpoint, yet its role in regulating macrophage function during malaria infection remains poorly understood.</p> Methods <p>We established a <i>Plasmodium yoelii</i> NSM murine model, in vitro co-culture systems, and comprehensive techniques including scRNA-seq, flow cytometry, and functional assays to investigate Tim-3 expression on splenic macrophages and its immunoregulatory impact.</p> Results <p>We observed a significant infection-induced downregulation of Tim-3 on splenic macrophages. Transcriptomic profiling revealed that Tim-3<sup>+</sup> macrophages exhibited enhanced antigen presentation and a proinflammatory phenotype characterized by elevated reactive oxygen species (ROS) and proinflammatory cytokine production. Blockade of Tim-3 in vivo exacerbated disease severity, increased parasitemia, and impaired macrophage phagocytic capacity, without directly affecting T-cell responses. Mechanistically, we identified transforming growth factor-beta (TGF-β) as a key upstream regulator of Tim-3 expression, as TGF-β signaling was suppressed during infection, and its stimulation or inhibition correspondingly upregulated or downregulated Tim-3. Furthermore, TGF-β-induced Tim-3 upregulation potentiated macrophage phagocytosis of infected red blood cells (iRBCs) and conferred protection against iRBC-induced cell death.</p> Conclusions <p>Our results reveal a novel protective TGF-β–Tim-3 axis that maintains the phagocytic function of macrophages and immune homeostasis in <i>Plasmodium yoelii</i> NSM infection. These findings highlight Tim-3 on macrophages as a potential therapeutic target for modulating host defense against malaria infection.</p> Graphical Abstract <p></p>

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TGF-β regulated Tim-3 sustains macrophage phagocytic function and confers protection in Plasmodium yoelii NSM-infected mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月27日

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  • Xiongyu Xie,
  • Guikuan Liang,
  • Mingjie Chen,
  • Lixin Luo,
  • Haiwen Yuan,
  • Shenao Chen,
  • Keyu Lu,
  • Wenbo Peng,
  • Long Xu,
  • Hongyan Xie,
  • Lu Li,
  • Shan Zhao,
  • Haixia Wei,
  • Xingfei Pan,
  • Jun Huang

摘要

Background

T-cell immunoglobulin and mucin domain 3 (Tim-3) is a critical immune checkpoint, yet its role in regulating macrophage function during malaria infection remains poorly understood.

Methods

We established a Plasmodium yoelii NSM murine model, in vitro co-culture systems, and comprehensive techniques including scRNA-seq, flow cytometry, and functional assays to investigate Tim-3 expression on splenic macrophages and its immunoregulatory impact.

Results

We observed a significant infection-induced downregulation of Tim-3 on splenic macrophages. Transcriptomic profiling revealed that Tim-3+ macrophages exhibited enhanced antigen presentation and a proinflammatory phenotype characterized by elevated reactive oxygen species (ROS) and proinflammatory cytokine production. Blockade of Tim-3 in vivo exacerbated disease severity, increased parasitemia, and impaired macrophage phagocytic capacity, without directly affecting T-cell responses. Mechanistically, we identified transforming growth factor-beta (TGF-β) as a key upstream regulator of Tim-3 expression, as TGF-β signaling was suppressed during infection, and its stimulation or inhibition correspondingly upregulated or downregulated Tim-3. Furthermore, TGF-β-induced Tim-3 upregulation potentiated macrophage phagocytosis of infected red blood cells (iRBCs) and conferred protection against iRBC-induced cell death.

Conclusions

Our results reveal a novel protective TGF-β–Tim-3 axis that maintains the phagocytic function of macrophages and immune homeostasis in Plasmodium yoelii NSM infection. These findings highlight Tim-3 on macrophages as a potential therapeutic target for modulating host defense against malaria infection.

Graphical Abstract